U.S. patent number 10,383,855 [Application Number 15/814,850] was granted by the patent office on 2019-08-20 for controlled release pharmaceutical formulations of nitozoxanide.
This patent grant is currently assigned to Romark Laboratories L.C.. The grantee listed for this patent is Romark Laboratories L.C.. Invention is credited to Marc Ayers, Jean-Francois Rossignol.
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United States Patent |
10,383,855 |
Rossignol , et al. |
August 20, 2019 |
Controlled release pharmaceutical formulations of nitozoxanide
Abstract
Solid dosage formulations of nitazoxanide or a nitazoxanide
analog are provided that comprise a controlled release portion and
an immediate release portion. The pharmaceutical composition is
typically in the form of a bilayer solid oral dosage form
comprising (a) a first layer comprising a first quantity of
nitazoxanide or analog thereof in a controlled release formulation;
and (b) a second layer comprising a second quantity of nitazoxanide
or analog thereof in an immediate release formulation. Method of
using the formulations in the treatment of hepatitis C are also
provided.
Inventors: |
Rossignol; Jean-Francois (St.
Petersburg, FL), Ayers; Marc (Tampa, FL) |
Applicant: |
Name |
City |
State |
Country |
Type |
Romark Laboratories L.C. |
Tampa |
FL |
US |
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Assignee: |
Romark Laboratories L.C.
(Tampa, FL)
|
Family
ID: |
42560126 |
Appl.
No.: |
15/814,850 |
Filed: |
November 16, 2017 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20180085353 A1 |
Mar 29, 2018 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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15141921 |
Apr 29, 2016 |
9827227 |
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13954184 |
Jul 30, 2013 |
9351937 |
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12656704 |
Feb 12, 2010 |
8524278 |
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61202285 |
Feb 13, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
1/16 (20180101); A61K 31/7056 (20130101); A61K
9/2086 (20130101); A61P 31/14 (20180101); A61K
9/2853 (20130101); A61K 38/21 (20130101); A61K
9/28 (20130101); A61K 31/426 (20130101); A61K
9/209 (20130101); A61K 9/284 (20130101); A61P
29/00 (20180101); A61K 9/4808 (20130101); A61P
43/00 (20180101); A61K 38/21 (20130101); A61K
2300/00 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61K
31/426 (20060101); A61K 9/28 (20060101); A61K
31/7056 (20060101); A61K 38/21 (20060101); A61K
9/24 (20060101); A61K 9/20 (20060101); A61K
9/48 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1438889 |
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Aug 2003 |
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0923934 |
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06-316517 |
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JP |
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2002-97132 |
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Apr 2002 |
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JP |
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2005-538121 |
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Dec 2005 |
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JP |
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2006-335771 |
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Dec 2006 |
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JP |
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WO 00/25752 |
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May 2000 |
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WO |
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WO 02/26214 |
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Apr 2002 |
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WO |
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WO 03/026637 |
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Apr 2003 |
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WO |
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WO 2004/012713 |
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Feb 2004 |
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WO |
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WO 2005/013935 |
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Feb 2005 |
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WO |
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WO 2007/020337 |
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Feb 2007 |
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WO |
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Other References
Chilukuri et al., Application No. 21-497 21-498/S-001, Clinical
Pharmacology and Biopharmaceutics Review(s), Jul. 14, 2014,
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-497_Alinia_BioP-
harmr.pdf, 35 pages. cited by applicant.
|
Primary Examiner: Richter; Johann R
Assistant Examiner: Sullivan; Danielle
Attorney, Agent or Firm: Foley & Lardner LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a Continuation of U.S. application Ser. No.
15/141,921, filed Apr. 29, 2016, which is a Continuation of U.S.
application Ser. No. 13/954,184, filed Jul. 30, 2013, which is a
Divisional of U.S. application Ser. No. 12/656,704, filed Feb. 12,
2010, which claims priority to U.S. Provisional Application No.
61/202,285, filed Feb. 13, 2009, the entire contents of which are
incorporated herein by reference.
Claims
What is claimed is:
1. A method for extending absorption of nitazoxanide, tizoxanide or
a combination thereof in a patient, the method comprising
administering to the patient a therapeutically effective amount of
a pharmaceutical composition in the form of a solid dosage form,
the composition comprising (a) a first portion comprising a first
quantity of nitazoxanide, tizoxanide or a combination thereof in a
controlled release formulation; and (b) a second portion comprising
a second quantity of nitazoxanide, tizoxanide or a combination
thereof in an immediate release formulation.
2. The method of claim 1, wherein each of the first and second
quantities comprises nitazoxanide.
3. The method of claim 2, wherein the first portion further
comprises a low viscosity polymer.
4. The method of claim 2, wherein the ratio of the first quantity
to the second quantity is about 2.5:1 to about 4:1.
5. The method of claim 2, wherein the first quantity of
nitazoxanide comprises about 500 mg of nitazoxanide; and the second
quantity of nitazoxanide comprises about 175 mg of nitazoxanide in
an immediate release formulation.
6. The method of claim 2, wherein the solid dosage form is a
bilayer tablet wherein: the first portion (a) forms a first layer
comprising about 500 mg of nitazoxanide in a controlled release
formulation, and further comprising a low-viscosity
hydroxypropylmethylcellulose; the second portion (b) forms a second
layer comprising about 175 mg of nitazoxanide in an immediate
release formulation, the second layer deposited on top of and
compressed with the first layer to form a core tablet.
7. The method of claim 6, wherein the tablet further comprises an
outer coating (c) applied to the core tablet.
8. The method of claim 2, wherein the solid oral dosage form is a
tablet.
9. The method of claim 2, wherein the solid oral dosage form is a
capsule.
10. The method of claim 9, wherein the first portion (a) is in the
form of controlled-release granules containing the first quantity
of nitazoxanide, and the second portion (b) is in the form of
immediate-release granules containing the second quantity of
nitazoxanide.
Description
BACKGROUND
Nitazoxanide (2-(acetolyloxy)-N-(5-nitro-2-thiazolyl) benzamide) is
a compound having the following structure:
##STR00001##
The preparation and uses of this compound are disclosed, for
example, in U.S. Pat. No. 3,950,351 to Rossignol.
Pharmaceutical compositions containing nitazoxanide and its
metabolite, tizoxanide, were originally developed and marketed for
treating intestinal parasitic infections.
Following oral administration of nitazoxanide or mixtures of
nitazoxanide plus tizoxanide in humans, these compounds are
partially absorbed from the intestinal tract, 4810-9382-4305.1 and
nitazoxanide is rapidly hydrolyzed to form tizoxanide in plasma.
Tizoxanide is glucurono-conjugated, and the drug is eliminated in
urine and bile as tizoxanide or tizoxanide glucuronide. The
half-life of tizoxanide in plasma is only approximately 1.5
hours.
For treating intestinal infections, pharmaceutical compositions
containing nitazoxanide or mixtures of nitazoxanide and tizoxanide
and a wetting agent and optionally a starch derivative have been
used successfully. The use of particles of active ingredients
ranging between 5 and 200 .mu.m was shown to be important to
achieving safety and efficacy. The use of a pharmaceutically
acceptable acid has been shown to improve the stability of these
pharmaceutical compositions. See, for example, U.S. Pat. Nos.
5,387,598; 5,968,961; and U.S. Pat. No. 6,117,894 to Rossignol.
Tablet and suspension formulations have been shown to be equally
effective for treating intestinal parasitic infections regardless
of their relative bioavailability.
The absorption of nitazoxanide and nitazoxanide-tizoxanide mixtures
from the intestinal tract varies significantly depending on the
pharmaceutical formulation. For example, the relative
bioavailability of an oral suspension has surprisingly been shown
to be only 70% of that of a tablet. Systemic bioavailability of
these compounds has not been of paramount importance, however,
because the compounds have been used almost exclusively for
treating parasites that reside in the lumen of the intestinal tract
or in the intestinal mucosa.
Nitazoxanide and tizoxanide have also been shown to be active in
vitro against certain DNA viruses in vitro (see, for example, U.S.
Pat. Nos. 5,578,621 and 5,886,013, to Rossignol). In recent years,
they were surprisingly shown to have activity against hepatitis C
virus (HCV), an RNA virus, in vitro and in clinical trials
(Reference pending US application, "Viral Hepatitis Treatment").
The mechanism of action of nitazoxanide and tizoxanide in
inhibiting virus replication is not known, but it has been
postulated to be a "cell-mediated" mechanism because of its broad
spectrum antiviral activity and the inability to induce
resistance.
Early clinical trials of nitazoxanide and tizoxanide in treating
chronic hepatitis C were conducted using a tablet formulation
developed for treatment of intestinal parasitic infections. That
tablet contained 500 mg of active ingredient (99% nitazoxanide/1%
tizoxanide). In patients chronically infected with HCV genotype 4,
sustained virologic response (SVR) rates of 61% to 80% were
achieved when the tablets were administered one tablet twice daily
for 4 to 12 weeks followed by the same regimen plus standard doses
of peginterferon .alpha.-2a with or without ribavirin for 36 weeks.
By contrast, patients treated with the standard therapy,
peginterferon .alpha.-2a plus ribavirin for 48 weeks, experienced
only a 50% SVR rate.
While early trials in patients with chronic hepatitis C genotype 4
showed improved efficacy using the 500 mg tablet, a significant
number of patients were not cured. Higher doses of active
ingredient could not be used to improve efficacy because previous
studies have shown that doses of 1000 mg twice daily are associated
with a significant increase in side effects, which are primarily
related to the intestinal tract (e.g., abdominal pain, diarrhea and
nausea). These side effects reduce patient compliance with the
treatment regimen and are particularly unacceptable for long-term
treatment of patients with hepatitis C.
For treating chronic HCV infection, tizoxanide must be delivered
into the bloodstream and to the infected hepatocytes. Ideally, the
drug should be administered by oral route no more often that twice
daily and without significant side-effects in order to maximize the
adherence of patients to the treatment regimen.
The variable absorption of nitazoxanide and tizoxanide in different
dosage formulations, the very short half-life of tizoxanide in
plasma and side-effects associated with high doses of nitazoxanide
and tizoxanide in the intestinal tract are problems that must be
overcome in developing a new optimized dosage formulation for
treating chronic hepatitis C. Furthermore, because the mechanism of
action of nitazoxanide against HCV is unknown, it is impossible to
know whether fluctuations in peak and trough concentrations at the
site of infection are beneficial or detrimental to improving
efficacy.
Thus, there is a need for a solid dosage formulation of
nitazoxanide and/or tizoxanide with improved efficacy in treating
chronic hepatitis C compared to tablets described in the prior art,
and without any increase in side effects.
SUMMARY
Controlled release formulations of nitazoxanide and nitazoxinide
analogues are described, as well as method of using the
formulations in the treatment of hepatitis C. In particular, solid
dosage formulations of nitazoxanide and nitazoxinide analogues are
described that comprise a controlled release portion and an
immediate release portion.
Thus, in some aspects, a pharmaceutical composition in the form of
a solid dosage form is provided, the composition comprising (a) a
first portion comprising a first quantity of nitazoxanide or an
analogue thereof in a controlled release formulation; and (b) a
second portion comprising a second quantity of nitazoxanide or an
analogue thereof in an immediate release formulation. In some
embodiments, the composition is a solid oral dosage form in the
form of a tablet or, in other embodiments, in the form of a
capsule.
In other aspects, a method is provided for treating a patient
suffering from hepatitis C, the method comprising administering to
the patient a therapeutically effective amount of a pharmaceutical
composition in the form of a solid dosage form, the composition
comprising (a) a first portion comprising a first quantity of
nitazoxanide or an analogue thereof in a controlled release
formulation; and (b) a second portion comprising a second quantity
of nitazoxanide or an analogue thereof in an immediate release
formulation.
In yet other aspects, a method is provided for treating a patient
suffering from hepatitis C, the method comprising (i) pretreating
the patient by administering to the patient for a period of time a
first composition in the form of a solid oral dosage form
comprising nitazoxanide or an analogue thereof as a first active
agent, wherein the first composition comprises (a) a first portion
comprising a first quantity of nitazoxanide or analogue thereof in
a controlled release formulation, and (b) a second portion
comprising a second quantity of nitazoxanide or analogue thereof in
an immediate release formulation; and (ii) after the period of time
in (i), administering to the patient a second composition
comprising a therapeutically effective amount of a second active
agent.
In some aspects, a method is provided for reducing one or more
side-effects associated with treatment with nitazoxanide or
tizoxanide in a patient, the method comprising administering to the
patient a therapeutically effective amount of a pharmaceutical
composition in the form of a solid dosage form, the composition
comprising (a) a first portion comprising a first quantity of
nitazoxanide or an analogue thereof in a controlled release
formulation; and (b) a second portion comprising a second quantity
of nitazoxanide or an analogue thereof in an immediate release
formulation.
In other aspects, a method is provided for increasing the
bioavailability of nitazoxanide or an analogue thereof in a
patient, the method comprising administering to the patient a
therapeutically effective amount of a pharmaceutical composition in
the form of a solid dosage form, the composition comprising (a) a
first portion comprising a first quantity of nitazoxanide or an
analogue thereof in a controlled release formulation; and (b) a
second portion comprising a second quantity of nitazoxanide or an
analogue thereof in an immediate release formulation.
In other aspects, a method is provided for extending absorption of
nitazoxanide or an analogue thereof in a patient, the method
comprising administering to the patient a therapeutically effective
amount of a pharmaceutical composition in the form of a solid
dosage form, the composition comprising (a) a first portion
comprising a first quantity of nitazoxanide or an analogue thereof
in a controlled release formulation; and (b) a second portion
comprising a second quantity of nitazoxanide or an analogue thereof
in an immediate release formulation.
In yet other aspects, a controlled release tablet for oral
administration is provided, the tablet comprising nitazoxanide or
an analogue thereof and a low-viscosity polymer, wherein the
low-viscosity polymer controls the release of the nitazoxanide or
analogue thereof.
DETAILED DESCRIPTION
The present compositions are controlled release solid formulations
of nitazoxanide or nitazoxanide analogues, in particular,
controlled release solid oral dosage forms comprising (a) a first
portion comprising a first quantity of nitazoxanide or an analogue
thereof in a controlled release formulation; and (b) a second
portion comprising a second quantity of nitazoxanide or an analogue
thereof in an immediate release formulation. The formulations are
typically in the form of a bilayer tablet for oral administration.
The compositions can be used to effectively treat chronic hepatitis
C and provide increased bioavailability and better absorption of
nitazoxanide, with fewer of the side effects commonly seen in
standard nitazoxanide formulations.
Unless otherwise specified, "a" or "an" means "one or more."
As used herein, the term "controlled release" refers to a property
of a pharmaceutical composition wherein the absorption and
bioavailability of the active agent in the composition is
maintained such that therapeutically effective amounts of the
active agent are bioavailable over an extended period of time.
As used herein, the term "immediate release" refers to a property
of a pharmaceutical composition wherein the active agent in the
composition is made bioavailable without substantial delay.
As used herein the terms "treating" and "treatment" refer to a
reduction in severity and/or frequency of symptoms, elimination of
symptoms and/or underlying cause, prevention of the occurrence of
symptoms and/or their underlying cause (e.g., prophylactic
therapy), improvement or remediation of damage, or reduction in
intensity of infection.
By the terms "effective amount" and "therapeutically effective
amount" of a compound of the invention is meant a nontoxic but
sufficient amount of the compound to provide the desired
effect.
By "pharmaceutically acceptable" is meant a material that is not
biologically or otherwise undesirable, i.e., the material may be
incorporated into a pharmaceutical composition administered to a
patient without causing any undesirable biological effects or
interacting in a deleterious manner with any of the other
components of the composition in which it is contained. When the
term "pharmaceutically acceptable" is used to refer to a
pharmaceutical carrier or excipient, it is implied that the carrier
or excipient has met the required standards of toxicological and
manufacturing testing or that it is included on the Inactive
Ingredient Guide prepared by the U.S. and Drug administration.
By "patient" is meant any animal for which treatment is desirable.
Patients may be mammals, and typically, as used herein, a patient
is a human individual.
The present solid compositions can comprise two portions, each
containing a quantity of nitazoxanide of nitazoxanide analogue.
Thus, in some embodiments, the compositions comprise a first
portion that contains nitazoxanide or analogue in a controlled
release formulation, and a second portion contains nitazoxanide
analogue in an immediate release formulation. In some embodiments,
the solid composition is in the form of a tablet in which the
immediate release portion is in the form of a layer that is
deposited on top of the controlled release portion, and compressed
to form a tablet. The solid dosage form can also be in the form of
a capsule containing both controlled release granules and immediate
release granules.
The present formulations contain nitazoxanide or an analogue
thereof as the active agent. Methods of preparing nitazoxanide are
known in those skilled in the art. See, e.g., U.S. Pat. No.
3,950,351 to Rossignol. Examples of nitazoxanide analogues and
methods of preparing them are disclosed in U.S. Pat. Nos. 7,285,567
and 6,117,894, and in published U.S. patent application nos.
2007/0167504, 2007/0015803, 2008/0097106, 2008/0096941, and
2009/0036467. Each of these U.S. patents and publications are
incorporated by reference herein in their entireties.
As used herein, the term "nitazoxanide" refers to both nitazoxanide
(2-(acetolyloxy)-N-(5-nitro-2-thiazolyl) benzamide) and to a
nitazoxanide analogue, e.g., to one of the compounds disclosed in
U.S. Pat. No. 7,285,567 or US 2007/0167504.
Nitazoxanide or any of the nitazoxanide analogues may be
administered in the form of the compound per se, and/or, where
suitable, in the form of a salt, polymorph, ester, amide, prodrug,
derivative, or the like, provided the salt, polymorph, ester,
amide, prodrug or derivative is suitable pharmacologically. Such
salts, esters, amides, prodrugs and other derivatives of these
active agents may be prepared using standard procedures known to
those skilled in the art of synthetic organic chemistry and
described, for example, by J. March, Advanced Organic Chemistry:
Reactions, Mechanisms and Structure, 4th Ed. (New York:
Wiley-Interscience, 1992). For any nitazoxanide analogue active
agents that may exist in enantiomeric forms, the active agent may
be incorporated into the present compositions either as the
racemate or in enantiomerically enriched form.
The total amount of nitazoxanide in the present compositions is
typically about 60% to 75% by weight of the composition. In those
embodiments having controlled release and immediate release
portions, the quantity of nitazoxanide in the controlled release
portion is typically greater than the quantity in the immediate
release portion, with the ratio of the quantity of nitazoxanide in
the controlled release portion to the nitazoxanide in the immediate
release portion being about 2.5-4.0:1. For example, in some
embodiments, the controlled release portion contains about 500 mg
of nitazoxanide, and the immediate release portion contains about
175 mg of nitazoxanide. In other embodiments, the controlled
release portion contains about 250 mg of nitazoxanide, and the
immediate release portion contains about 87.5 mg of
nitazoxanide.
The compositions can contain one or more additional
pharmaceutically acceptable additives or excipients. In those
embodiments with controlled release and immediate release portions,
both the controlled release portion and the immediate release
portion can contain one or more additional pharmaceutically
acceptable additives or excipients. These excipients are
therapeutically inert ingredients that are well known and
appreciated in the art. As used herein, the term "inert ingredient"
refers to those therapeutically inert ingredients that are well
known in the art of pharmaceutical science, which can be used
singly or in various combinations, and include, for example,
diluents, disintegrants, binders, suspending agents, glidants,
lubricants, fillers, coating agents, solubilizing agent, sweetening
agents, coloring agents, flavoring agents, and antioxidants. See,
for example, Remington: The Science and Practice of Pharmacy 1995,
edited by E. W. Martin, Mack Publishing Company, 19th edition,
Easton, Pa.
Examples diluents or fillers include, but are not limited to,
starch, lactose, xylitol, sorbitol, confectioner's sugar,
compressible sugar, dextrates, dextrin, dextrose, fructose,
lactitol, mannitol, sucrose, talc, microcrystalline cellulose,
calcium carbonate, calcium phosphate dibasic or tribasic, dicalcium
phosphate dehydrate, calcium sulfate, and the like.
Diluent(s) or filler(s) typically represent about 10% to 15% by
weight of the controlled release or immediate release portion, or
about 2% to about 15% by weight of the entire composition.
Examples of disintegrants include, but are not limited to, alginic
acid, methacrylic acid DVB, cross-linked PVP, microcrystalline
cellulose, sodium croscarmellose, crospovidone, polacrilin
potassium, sodium starch glycolate, starch, including corn or maize
starch, pregelatinized starch and the like.
Disintegrant(s) typically represent about 10% to 15% by weight of
the controlled release or immediate release portion, or about 2% to
about 15% by weight of the entire composition.
Examples of binders include, but are not limited to, starches such
as potato starch, wheat starch, corn starch; microcrystalline
cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl
cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose,
sodium carboxy methyl cellulose; natural gums like acacia, alginic
acid, guar gum; liquid glucose, dextrin, povidone, syrup,
polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide,
polyethylene glycol, gelatin, poly propylene glycol, tragacanth,
and the like.
Binder(s) typically represent about 2% to 15% by weight of the
controlled release or immediate release portion, or about 0.2% to
about 14% by weight of the entire composition.
Examples of glidants include, but are not limited to, silicon
dioxide, colloidal anhydrous silica, magnesium trisilicate,
tribasic calcium phosphate, calcium silicate, magnesium silicate,
colloidal silicon dioxide, powdered cellulose, starch, talc, and
the like.
Glidant(s) typically represent about 0.1% to 0.5% by weight of the
controlled release or immediate release portion, or about 0.01% to
about 0.3% by weight of the entire composition.
Examples of lubricants include, but are not limited to, magnesium
stearate, aluminum stearate, calcium stearate, zinc stearate,
stearic acid, polyethylene glycol, glyceryl behenate, mineral oil,
sodium stearyl fumarate, talc, hydrogenated vegetable oil and the
like.
Lubricant(s) typically represent about 0.5% to 1.5% by weight of
the controlled release or immediate release portion, or about 0.2%
to about 1.0% by weight of the entire composition.
For example, in some embodiments, the controlled release portion,
the immediate release portion, or both contain a starch as the
diluent, such as corn or maize starch; sodium croscarmellose and
the disintegrant; hydroxypropylcellulose, microcrystalline
cellulose, and/or hydroxypropyl methylcellulose and the binder(s);
dicalcium phosphate dehydrate as the filler; colloidal anhydrous
silica as the glidant; and magnesium stearate as the lubricant.
The present controlled release compositions also contains a binder
that is a low-viscosity polymer. Examples of low-viscosity polymers
include, but are not limited to, low-viscosity hydroxypropyl
methylcellulose polymers such as those sold by Dow Chemical under
the tradename "Methocel.RTM." (e.g., Methocel E50LV.RTM., Methocel
K100LV.RTM., and Methocel F50LV.RTM.) and low-viscosity
hydroxyethylcellulose polymers. The low-viscosity polymer controls
the release of the nitazoxanide or analogue thereof in the
formulation.
The low-viscosity polymer is typically present at about 10% to
about 20%, or about 10% to about 15%, or preferably about 12%, of
the total weight of the entire composition, or, in those
embodiments having controlled release and immediate release
portions, the low-viscosity polymer in the controlled release
portion is typically present at about 15% to about 20%, preferably
about 18%, of the weight of the controlled release portion.
The present compositions can further comprise a coating material.
The coating material is typically present as an outer layer on the
dosage form that completely covers the formulation. For example, in
some embodiments, the dosage form is an oral tablet in which the
controlled release portion forms a first layer of the tablet and
the immediate release portion forms a second layer that is
deposited on top of the first layer to form a core tablet. In such
embodiments, e.g., the coating material can be in the form of an
outer coating layer that is deposited on top of the core
tablet.
The coating material typically is about 1% to about 5% by weight of
the composition.
The coating material can comprise hydroxypropylmethylcellulose
and/or polyethylene glycol, and can comprise one or more excipients
selected from the group comprising coating agents, opacifiers,
taste-masking agents, fillers, polishing agents, coloring agents,
antitacking agents and the like. For example, the coating material
can contain titanium dioxide as an opacifying agent. Examples of
film-coating substances and methods for using such coating
substances are well known to those of skill in the art.
For example, the coating material used in the present compositions
can be OPADRY AMB 80W91416 or OPADRY FX 63F97546, as in the
examples below.
Methods of making solid pharmaceutical formulations are known to
those of skill in the art of pharmaceutical formulations and can be
employed to prepare the present compositions. See, for example,
Remington: The Science and Practice of Pharmacy (1995), edited by
E. W. Martin, Mack Publishing Company, 19th edition, Easton,
Pa.
The present compositions can be used to effectively treat chronic
hepatitis C and provide increased bioavailability and better
absorption of nitazoxanide, with fewer of the side effects commonly
seen in standard nitazoxanide formulations.
The compositions may be administered for any length of time
suitable for effective for treatment of hepatitis C. Any
appropriate dosage and regimen may be used for the compositions.
Administration can typically be carried out over a period of about
3 days to about 104 weeks, but may be carried out over a period
longer than 104 weeks and may even be carried out indefinitely. For
example, treatment of hepatitis C using the present formulations
will typically involve administration of the formulations over a
period of 12, 24, or 48 weeks. Appropriate regimens can be
determined by a physician.
One or more additional active agents may be included in the present
pharmaceutical compositions and methods of treatment. For example,
in some embodiments, the compositions may include one or more
additional therapeutic agents useful in treating hepatitis C such
as ribavirin, and immune-stimulating agents including, but not
limited to, interferons such as interferon .alpha.-2b, a derivative
of interferon .alpha.-2b such as a polyethylene glycol-conjugated
form of interferon .alpha.-2b, interferon .alpha.-2a, or interferon
alfacon-1.
The composition and the additional active agent (e.g., an
interferon) may be administered simultaneously, or separately, at
the same time, or in different compositions (including in separate
compositions that vary in dosage form, release profiles, and the
like).
For example, in some embodiments, a patient suffering from
hepatitis C is first pretreated with one of the nitazoxanide
compositions described herein. The duration of the pretreatment
period may be between about 3 days and about 6 months, for example,
between about 1 week and about 12 weeks, and, as a further example,
between about 1 week and about 4 weeks. The pretreatment period can
be followed subsequently by a treatment period wherein the
pretreated patient is treated with either an interferon alone or an
interferon plus nitazoxanide and, optionally, one or more
additional agents such as an antiviral agent, e.g., ribavirin. Any
of the interferons described herein may be used during the
treatment period. The duration of the treatment period can be any
duration that is required to obtain the desired response, and will
typically be between about 1 day and about 12 months or longer. For
example, the treatment period may comprise weekly injections of an
interferon, and may involve a single week of treatment, 2-4 weeks
of treatment, 4-12 weeks of treatment, or more (such as 6 months, 1
year, 2 years, or indefinitely).
It is to be understood that the description above as well as the
examples that follow are intended to illustrate and not limit the
scope of the invention. Other aspects, advantages and modifications
within the scope of the invention will be apparent to those skilled
in the art to which the invention pertains.
EXAMPLES
Example 1
Factors Affecting Bioavailability of Nitazoxanide
A study was performed to investigate the impact of each of the
following factors on bioavailability of nitazoxanide: (1)
absorption of tizoxanide vs. nitazoxanide, (2) modifying site of
release in GI tract, (3) effect of different polymers, and (4)
effect of granulation in alcohol vs. water.
Six different nitazoxanide and/or tizoxanide formulations were
administered orally with food to four healthy adult male volunteers
to investigate each factor. Each of the volunteers received each of
the six formulations in six different treatment periods, each
treatment period being separated by at least one week. The
formulations were administered orally with food. Blood samples were
taken at eleven time points: immediately before the dose and at 1,
2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post-dose. The following
formulations were administered:
(1) an immediate-release ("IR") nitazoxanide/tizoxanide tablet
containing 500 mg of 99% nitazoxanide/1% tizoxanide as active
ingredient;
(2) an immediate-release tizoxanide tablet containing 500 mg of
tizoxanide as active ingredient;
(3) an enteric-coated IR nitazoxanide/tizoxanide tablet coated with
ACRYL-EZE.RTM. 70 mg (10% weight gain);
(4) a nitazoxanide/tizoxanide tablet containing 500 mg of 99%
nitazoxanide, 1% tizoxanide as active ingredient, granulated in
alcohol with hydroxypropyl-methylcellulose (Metolose 90 SH) 100.000
SR as binding agent and dicalciumphosphate dihydrate as filler;
(5) a nitazoxanide/tizoxanide tablet containing 500 mg of 99%
nitazoxanide, 1% tizoxanide as active ingredient, granulated in
water with hydroxypropyl-methylcellulose (Metolose 90 SH) 100.000
SR as binding agent and dicalciumphosphate dihydrate as filler;
and
(6) a nitazoxanide/tizoxanide tablet containing 450 mg of 99%
nitazoxanide, 1% tizoxanide as active ingredient, granulated in
water with hydroxypropyl-methylcellulose (Methocel K100LV), 100 cP
as binding agent and dicalciumphosphate dihydrate as filler (two
tablets were administered to the patients).
Serum pharmacokinetic (PK) parameters were calculated from blood
samples taken from the volunteers. Median values for AUC.sub.t
(.mu.ghr/mL), C.sub.max (.mu.g/mL), C.sub.min (.mu.g/mL), and
T.sub.max (hr) are presented in Table 1.
TABLE-US-00001 TABLE 1 Median serum pharmacokinetic parameter
values for tizoxanide following administration of six different
pharmaceutical formulations containing nitazoxanide and/or
tizoxanide to four healthy adult male volunteers AUC.sub.t
C.sub.max C.sub.min T.sub.max Formulation .mu.g*hr/mL .mu.g/mL
.mu.g/mL (hr) (1) IR tablet, 500 mg.sup.1 38.07 9.75 0.05 3 (2)
Tizoxanide, 500 mg.sup.2 9.12 1.81 0.00 4 (3) Enteric coated IR
tablet, 500 26.97 6.50 0.00 8 mg.sup.3 (4) High-viscosity polymer
(dry 2.88 0.72 0.00 7 granulated), 500 mg .sup.4 (5) High-viscosity
polymer 2 (wet 6.14 1.49 0.00 8 granulated), 500 mg .sup.5 (6)
Low-viscosity polymer (900 34.77 7.03 0.21 7 mg, 2 .times. 450 mg
tablets) .sup.6 .sup.1Standard immediate release tablet containing
approximately 500 mg of active ingredient, which is 99%
nitazoxanide/1% tizoxanide. .sup.2Same formulation as IR tablet,
except that active ingredient is 100% tizoxanide. .sup.3IR tablet
coated with ACRYL-EZE .RTM. 70 mg (10% weight gain). .sup.4 500 mg
of active ingredient (99% nitazoxanide, 1% tizoxanide) granulated
in alcohol with hydroxypropyl-methylcellulose (HPMC), 100,000
centipoise ("cP") (Metolose 90 SH 100.000 SR) as binding agent and
dicalciumphosphate dihydrate as filler .sup.5 500 mg of active
ingredient (99% nitazoxanide, 1% tizoxanide) granulated in water
with HPMC, 100,000 cP (Metolose 90 SH 100.000 SR) as binding agent
and dicalciumphosphate dihydrate as filler .sup.6 450 mg of active
ingredient (99% nitazoxanide, 1% tizoxanide) granulated in water
with HPMC, 100 cP (Methocel K100LV). Two tablets were administered
to these patients.
Surprisingly, bioavailability was much lower following oral
administration of tizoxanide (Formulation 2) compared to
nitazoxanide (Formulation 1).
The enteric coating of the IR nitazoxanide/tizoxanide tablet
(Formulation 3) delayed absorption in two patients as evidenced by
the increase in T.sub.max from 3 to 8 hours, but it also prevented
absorption in the other two patients.
The high-viscosity polymer (HPMC 100,000 cP) in Formulations 4 and
5 essentially prevented absorption.
Granulation in water using the high-viscosity polymer (Formulation
5) improved absorption compared to granulation in alcohol
(Formulation 4).
Reduction of viscosity of HPMC to 100 cP (Formulation 6) resulted
in a significant improvement in absorption (AUC.sub.t), but
absorption was still inferior to that of the IR tablet.
Furthermore, even with delayed absorption and use of a higher 900
mg dose, tizoxanide was eliminated rapidly from serum so that the
tizoxanide concentration in serum at 12 hours post-dose was below 2
.mu.g/mL in all 4 patients (median 1.28 .mu.g/mL).
Example 2
Bilayer Tablet Formulation
A bilayer tablet containing a total of 650 mg of nitazoxanide was
made using standard formulation techniques, as described above. The
composition of the bilayer tablet is presented in Table 2.
TABLE-US-00002 TABLE 2 Composition of Nitazoxanide 675 mg
controlled release tablet. Unit formula Reference to INGREDIENTS
(mg/tablet) Function Standards* Immediate Release Layer
Nitazoxanide 175 Active Monograph substance Non-active substances:
Maize starch 36 Diluent/ Ph. Eur. 0344 disintegrant
Hydroxypropylcellulose 5 Binder/ Ph. Eur. 0337 (Klucel EF)
suspending agent Sodium croscarmellose 7.5 Disintegrant Ph. Eur.
0985 Colloidal anhydrous silica 1 Glidant Ph. Eur. 0434 (Aerosil
200) Microcrystalline cellulose 23 Dry binder Ph. Eur. 0316
Magnesium stearate 2.5 Lubricant Ph. Eur. 0229 Water, Purified 50
Solvent Ph. Eur. 0008 Controlled Release Layer Nitazoxanide 500
Active Monograph substance Non-active substances:
Hydroxypropyl-cellulose 2.5 Binder/ Ph. Eur. 0337 (Klucel EF)
suspending agent Hydroxypropyl- 135 Binder/ Ph. Eur. 0348
methylcellulose suspending (Methocel E50LV) agent
Dicalciumphosphate 102.5 Filler Ph. Eur. 0116 dihydrate
(Emcompress) Colloidal anhydrous silica 3 Glidant Ph. Eur. 0434
(Aerosil 200) Magnesium stearate 7 Lubricant Ph. Eur. 0229 Water,
Purified 60 Solvent Ph. Eur. 0008 Coating Materials OPADRY AMB 40
Coating In house 80W91416, GREEN Monograph (contains c.i. pigment
blue 63, polyvinyl alcohol, talc, lecithins, xanthan gum, titanium
dioxide, c.i. pigment yellow 42) OPADRY FX 63F97546, 5 Coating In
house Gloss (contains polyvinyl Monograph alcohol, talc,
polyethylene glycol, mica-based pearlescent pigment, polysorbate
80) Water, Purified 326 Solvent Ph. Eur. 0008 *References are to
current editions.
Example 3
Batch Formulation of Bilayer Tablets
A batch of 100,000 nitazoxanide bilayer tablets (650 mg) of Example
2 was prepared as indicated in Table 3.
TABLE-US-00003 TABLE 3 Manufacturing batch formula for Nitazoxanide
675 mg controlled release tablets Unit formula Batch Formula
INGREDIENTS (mg/tablet) (100,000 tablets) Immediate Release Layer
Nitazoxanide 175 17.5 kg Non-active substances: Maize starch 36 3.6
kg Hydroxypropylcellulose (Klucel EF) 5 0.5 kg Sodium
croscarmellose 7.5 0.75 kg Colloidal anhydrous silica (Aerosil 200)
1 0.1 kg Microcrystalline cellulose 23 2.3 kg Magnesium stearate
2.5 0.25 kg Water, Purified 50 5 kg Controlled Release Layer
Nitazoxanide 500 50 kg Non-active substances:
Hydroxypropyl-cellulose (Klucel EF) 2.5 0.25 kg
Hydroxypropyl-methylcellulose 135 13.5 kg (Methocel E50LV)
Dicalciumphosphate dihydrate 102.5 10.25 kg (Emcompress) Colloidal
anhydrous silica (Aerosil 200) 3 0.3 kg Magnesium stearate 7 0.7 kg
Water, Purified 60 6 kg Coating Materials: OPADRY AMB 80W91416,
GREEN 40 4 kg contains c.i. pigment blue 63, polyvinyl alcohol,
talc, lecithins, xanthan gum, titanium dioxide, c.i. pigment yellow
42 OPADRY FX 63F97546, Gloss 5 0.5 kg (contains polyvinyl alcohol,
talc, polyethylene glycol, mica-based pearlescent pigment,
polysorbate 80) Water, Purified 326 32.6 kg
The tablets were produced following the manufacturing protocol
outlined below.
A. Equipment
Frewitt sieve Collette Planetary blender Drying oven Tabletting
machine--Manesty BB press Tablet deduster Coating
apparatus--Accelacota
All production equipment is cleaned prior to use.
B. Preparation of Immediate Release Granulate (Granulate A)
1. The raw materials are weighed into sealed plastic bags. 2. The
integrity of the machine is checked before and after use. 3. If
necessary, the nitazoxanide and maize starch are sieved through a
1.25 mm mesh sieve using a Frewitt machine. 4. These ingredients
are transferred to the bowl of a Collette Planetary Blender and
blended for 15 minutes at low speed. 5. Dissolve
hydroxypropylcellulose (HPC) in water, allow to stand overnight. 6.
This HPC solution is slowly added with mixing and the content is
mixed for 5-10 minutes at low speed. 7. If necessary, add extra
water. 8. The granulate is sieved through a 4 mm mesh sieve using a
Frewitt machine, put on trays and dried at 50.degree. C. for 12 to
16 hours. 9. The trays are removed from the oven, samples are taken
to test for loss on drying. 10. The dried granulate is re-sieved
through a 1.25 mm mesh sieve using a Frewitt machine and
transferred to the drum of the blender. 11. The aerosil, sodium
croscarmellose and microcrystalline cellulose are sieved through a
1.25 mm mesh sieve using a Frewitt machine and added to the above
and mixed for 15 minutes at low speed. 12. Magnesium stearate is
sieved through a 1.25 mm mesh sieve using a Frewitt machine and
added to the above and mixed for 4 minutes at low speed. C.
Preparation of Controlled Release Granulate (Granulate B) 1. The
raw materials are weighed into sealed plastic bags. 2. The
integrity of the machine is checked before and after use. 3.
Nitazoxanide is transferred to the bowl of a Collette Planetary
Blender. 4. Dissolve HPC in water, allow to stand overnight. 5. The
HPC solution is slowly added with mixing and the content is mixed
for 5-10 minutes at low speed. 6. If necessary, add extra water. 7.
The granulate is sieved through a 4 mm mesh sieve using a Frewitt
machine, put on trays and dried at 50.degree. C. for 12 to 16
hours. 8. The trays are removed from the oven, samples are taken to
test for loss on drying. 9. The dried granulate is re-sieved
through a 1.25 mm mesh sieve using a Frewitt machine and
transferred to the drum of the blender. 10.
Hydroxypropylmethylcellulose, dicalciumphosphate dihydrate and
aerosil are sieved through a 1.25 mm mesh sieve using a Frewitt
machine. 11. These ingredients are added to the bowl of the Colette
Planetary Blender and blended for 15 minutes at low speed. 12.
Magnesium stearate is sieved through a 1.25 mm mesh sieve using a
Frewitt machine and added to the above and mixed for 4 minutes at
low speed. D. Tabletting 1. The tabletting is carried out using a
Manesty BB press tabletting machine (19 mm oblong biconvex punch).
2. Filling and precompression of granulate B: target weight=750 mg
second filling with granulate A: target weight=250 mg and final
compression: final weight=1000 mg
The pressure is adjusted after visual inspection. 1. The tablets
are dedusted. 2. Tablets are taken for weight control, friability,
assay, thickness and hardness. 3. The gross and net weight of
tablets produced is recorded. If these are not within .+-.5% of
limits, reasons for losses must be recorded. E. Coating 1. Verify
the identity of the material used for manufacturing and the line
clearance. 2. The tablets are transferred to the coating apparatus
(Accelacota). 3. Prepare the coating suspension as follows:
Transfer purified water into a suitable container. Disperse the
OPADRY AMB 80W91416, GREEN by means of rapid stirring. After all
the OPADRY has been added, continue stirring for a further 45
minutes. 4. Pour the coating suspension into the coating apparatus
(Accelacota). 5. Mix gently while the coating suspension is being
sprayed. 6. Repeat step 32-34 with OPADRY FX 63F97546, Gloss. 7.
Afterwards, verify the weight increase of 100 tablets. The increase
must be at least 35 mg/tablet. 8. Sampling and control of unit
weight and disintegration. 9. After approval by Quality Assurance,
transfer the tablets into clean containers, lined with two
polyethylene bags.
Example 4
Testing of Final Bilayer Tablets
The 675 mg nitazoxanide bilayer tablet described in Examples 2 and
3 ("NTZ 675 mg tablet") was tested in the following two clinical
studies.
1. Study RM06-1001 (Pharmacokinetics and Tolerability Study in
Healthy Volunteers Using 675 mg Controlled Release Tablets).
12 healthy adult volunteers were randomized in double-blind fashion
to receive one NTZ 675 mg tablet and one placebo tablet b.i.d. or
two NTZ 675 mg tablets b.i.d. for 7 days. After a 7-day washout
period, each subject crossed over to receive 7 days of treatment
with the dose that he had not received during the first 7-day
treatment period. Plasma samples were collected for assay of NTZ
metabolites, tizoxanide (T) and tizoxanide glucuronide (TG), over
12 hours following the first dose on day 1, before the morning dose
on day 5 and day 6 and over 24 hours following the morning dose on
day 7 (the last dose).
The following table presents important pharmacokinetic parameters
for tizoxanide obtained after 7 days administration of the
controlled release tablets compared to results obtained from a
similar study using the nitazoxanide 500 mg immediate release
("IR") tablet (Study 198.637). The total exposure (AUC) and minimum
plasma concentrations (C.sub.min) were significantly higher for the
controlled release tablet than for the IR tablet, but the maximum
plasma concentrations were similar.
TABLE-US-00004 TABLE 4 Comparison of Important Pharmacokinetics
Parameters for Tizoxanide from Study RM06-1001 to Historical Data
from a Similar Study of the Nitazoxanide 500 mg Immediate Release
Tablets CR Tablet IR Tablet 675 mg 1350 mg 500 mg 1000 mg b.i.d.
b.i.d. b.i.d. b.i.d. (n = 12) (n = 11) (n = 6) (n = 5)
AUC.sub..infin.(.mu.g h/mL) 78.3 221 52.3 158 C.sub.min (.mu.g/mL)
1.26 5.39 0.40 2.14 C.sub.max (.mu.g/mL) 11.9 29.8 9.3 24.4
The values presented in Table 4 are arithmetic means. Data for CR
tablet were taken from study RM06-1001. Data for IR tablet was
taken from study 198.637. In both studies, the tablets were
administered b.i.d. with food for 7 days in healthy adult male
volunteers. The pharmacokinetic parameters presented are for day 7
of b.i.d. dosing.
Only mild to moderate adverse events were observed in Study
RM06-1001, the most common being chromaturia, fatigue, diarrhea,
conjunctival discoloration, abdominal pain and nausea. Adverse
events occurring with greater frequency during the high dose
treatment were: diarrhea (8 [73%] versus 4 [33%] subjects), nausea
(7 [64%] versus 3 [25%] subjects), abdominal pain (6 [55%] versus 2
[17%] subjects), and decreased appetite (4 [36%] versus 1 [8%]
subjects). The occurrence rates of all other adverse events were
similar for the two treatment regimens. There were no significant
changes in clinical laboratory values, vital signs or ECG
parameters.
Historically, the most common adverse events associated with oral
administration of nitazoxanide have been related to the
gastrointestinal tract. The following table presents the most
common gastrointestinal adverse events reported from Study
RM06-1001 alongside those reported in Study 198.637 using the 500
mg immediate release (IR) tablet. The data in Table 5 indicate that
the controlled release tablet is better tolerated than the
immediate release tablet.
TABLE-US-00005 TABLE 5 Comparison of Numbers of Patients Reporting
Most Common Gastrointestinal Adverse Events from Phase I Clinical
Studies in Healthy Male Volunteers: Studies RM06-1001 and 198.637
Placebo CR Tablet IR Tablet CR Tablet IR Tablet IR Tablet 675 mg
500 mg 1350 mg 1000 mg BID BID BID BID BID (n = 4) .sup.1 (n = 12)
.sup.2 (n = 6) .sup.1 (n = 11) .sup.2 (n = 6) .sup.1 Abdominal 1,
25% 2, 17% 3, 50% 6, 55% 6, 100% pain Diarrhea 2, 50% 4, 33% 4, 67%
8, 73% 5, 83% Flatulence 2, 50% 0, 0% 1, 17% 0, 0% 4, 67% Nausea 0,
0% 3, 25% 0, 0% 7, 64% 4, 67% Total 5 9 8 21 21 Total/n 1.25 0.75
1.25 1.91 3.5 Moderate 0, 0% 0, 0% 0, 0% 4, 37% 3, 50% AEs.sup.3
Discontin- 0, 0% 0, 0% 0, 0% 0, 0% 1, 17% uations.sup.4 .sup.1 From
study 198.637. .sup.2 From study RM06-1001. .sup.3All other adverse
events were mild. .sup.4Discontinuations due to adverse events.
Data for the CR tablet was taken from study RM06-1001 (final report
in preparation). Data for the IR tablet and the placebo tablets
were taken from study 198.637. In both studies, the tablets were
administered b.i.d. with food for 7 days in healthy adult male
volunteers. Both studies were conducted at the same clinical center
by SGS Biopharma (CRO), and both studies were double-blinded so
that neither the patients or physicians were aware of treatment
group assignment. The study of the IR tablet was conducted in 1998,
and the study of the CR tablet was conducted in 2008.
2. Study RM06-1002 (Viral Kinetics Study in Patients with Chronic
Hepatitis C Genotype 4 Using 675 mg Controlled Release
Tablets).
40 interferon-naive patients with chronic hepatitis C genotype 4
were randomized (2:2:1) in double-blind fashion to receive NTZ 675
mg b.i.d. for 4 weeks followed by NTZ 675 mg b.i.d. +PegIFN+RBV for
48 weeks, NTZ 1350 mg b.i.d. for 4 weeks followed by NTZ 1350 mg
b.i.d. +PegIFN+RBV for 48 weeks, or placebo b.i.d. for 4 weeks
followed by placebo+PegIFN+RBV for 48 weeks. Dosing of PegIFN
(peginterferon alfa-2a, Pegasys.RTM., Roche, Basel, Switzerland)
was 180 .mu.g/week, and dosing of RBV (Viracure.RTM., October
Pharma, Cairo, Egypt) was 1000 mg/day (weight <75 kgs), or 1200
mg/day (body weight .gtoreq.75 kgs). HCV RNA was quantified at
baseline and on days 3, 7, 14 and 28 during the monotherapy lead-in
phase and on days 3, 7, 14 and 28 of the combination therapy phase.
The primary endpoint was the change in quantitative HCV RNA from
baseline to week 4 of combination therapy. Secondary endpoints
included RVR (HCV RNA<12 IU/mL after 4 weeks of combination
therapy), cEVR (HCV RNA<12 IU/mL after 12 weeks of combination
therapy) and EVR (.gtoreq.2 log.sub.10 drop in HCV RNA after 12
weeks of combination therapy). HCV RNA was quantified using the
Abbott Realtime HCV RT-PCR assay (LOD=12 IU/mL)
Virologic response through study week 16 is described in the table
below.
TABLE-US-00006 TABLE 6 Virologic Response to Treatment Using
Controlled Release Tablets 1350 mg BID + 675 mg BID + Placebo + PEG
+ RBV PEG + RBV PEG + RBV (n = 16) (n = 17) (n = 8) Mean reduction
of HCV -4.4 -3.9 -3.5 RNA from baseline to week 4 of combination
therapy (log10 IU/mL) RVR 10 (63%) 10 (59%) 4 (50%) cEVR 16 (100%)
14 (82%) 5 (63%) EVR 16 (100%) 15 (88%) 5 (63%)
No serious adverse events were reported, and no patients
discontinued treatment due to an adverse event.
This study demonstrated a dose-related improvement in virologic
response to therapy. In a previous study in patients with chronic
hepatitis C genotype 4 who were treated with the IR tablet twice
daily plus peginterferon alfa-2a and ribavirin, the proportion of
patients achieving undetectable levels of HCV RNA after 12 weeks of
combination therapy (cEVR) was 86% ( 24/28). Use of the new
controlled release tablet formulation with fewer side effects
allowed us to increase the dose of active ingredient to 1350 mg
twice daily, improving the concentrations of tizoxanide in plasma
and improving the proportion of patients achieving cEVR.
Although the foregoing refers to particular preferred embodiments,
it will be understood that the present invention is not so limited.
It will occur to those of ordinary skill in the art that various
modifications may be made to the disclosed embodiments and that
such modifications are intended to be within the scope of the
present invention.
All of the publications, patent applications and patents cited in
this specification are incorporated herein by reference in their
entirety.
* * * * *
References